phase iii trial assessing the efficacy and safety of pxt3003 in cmt1a patients

Conditions: Charcot-Marie-Tooth Disease

Summary: the study will consist of 2 periods: double-blind treatment and open-label extension(ole) period. -double-blind treatment period - this will be randomized, double-blind, placebo-controlled part of the study which will be conducted in parallel groups, ie,1 group receiving the active treatment (pxt3003) and the other group receiving placebo. primary endpoint of the study will be assessed at month 15. -open-label extension (ole) period - all subjects completing double-blind treatment period will be given an opportunity to enter the ole period of the study and receive the active treatment (pxt3003). the duration of the ole period will be based on sponsor discretion, ie, sponsor intends to keep the study open until the study drug pxt3003 is commercially available. during this period, the long-term safety and efficacy of pxt3003 will be assessed as an exploratory objective. double-blind treatment period objectives: primary: to evaluate the efficacy of treatment with pxt3003 (a fixed-dose combination of \[rs\]-baclofen, naltrexone hydrochloride \[hcl\], and d-sorbitol) compared to placebo in subjects with charcot-marie-tooth disease type 1a (cmt1a). secondary: to evaluate the safety and tolerability of pxt3003 treatment in subjects with cmt1a. exploratory: to characterize the relationship between plasma biomarkers and response to pxt3003 treatment. ole period objective: exploratory: to evaluate the long-term safety and efficacy of pxt3003.

this is an international, multi-center, randomized, double-blind, placebo-controlled, parallel-group, phase iii study of pxt3003 in subjects with cmt1a. the study will be conducted at approximately 52 sites worldwide. this study consists of double-blind treatment and ole periods. double-blind treatment period: eligible subjects will be screened and randomized in a 1:1 ratio to receive either oral pxt3003 or matching placebo, 10 ml, twice daily (bid) for 15 months. in order to maximize the tolerability of (rs)-baclofen for all randomized subjects, treatment will start with a half-dose (5 ml), taken bid (morning and evening with food) during the first 2 weeks, and then will be increased to a full-dose (10 ml), taken bid (morning and evening with food) until completion of the treatment period at month 15. a total of approximately 350 subjects will be enrolled. visits will take place at screening (up to -35 days), baseline (day 1), and months 3, 6, 9, 12, and 15. telephone contacts will take place at weeks 2 or 3, month 1 and month 2, and then monthly between subsequent in-person visits. a genotyping test for the peripheral myelin protein 22 (pmp22) gene duplication will take place at the screening visit if it is not already documented for the subject. all subjects completing the double-blind treatment period of the study will be given an opportunity to enter the ole period at month 15 (visit 6). subjects not consenting to enter the ole period will have their last study visit (ie, safety follow-up visit, visit 7), 30 days after their last dosing day. the primary outcome measures modified overall neuropathy limitations score(monls) and the 10-meter walk test (10mwt), along with the columbia suicide severity rating scale (c-ssrs) will be evaluated at each post-randomization in-person visit. the other secondary outcome measures, exploratory outcome, and safety/tolerability assessments will be evaluated as per schedule of activities (soa). a data safety and monitoring board (dsmb) will meet on a scheduled basis throughout the study to review safety data and will reconvene on an ad hoc basis as necessary. planned duration for sites to enroll subjects: approximately 12 months, subject screening period: 35 days, subject treatment period: up to 15 months, safety follow-up period (for subjects not entering the ole period): 30 days ole period: a subject entering the ole period (whether the subject was randomized to oral pxt3003 or matching placebo in the double-blind treatment period) will start taking a half-dose of pxt3003 (5 ml) bid (morning and evening with food) during the first 2 weeks, and then a full dose of pxt3003 (10 ml) bid (morning and evening with food) throughout the ole period. the visits and assessments during the ole period are described in the soa. for subjects entering the ole period, screening day will occur on the same day as visit 6 (month 15) of the double-blind treatment period. the duration of the treatment period will be based on sponsor discretion. sponsor intends to keep the study open until the study drug pxt3003 is commercially available. safety follow-up period: 30 days

Eligibility criteria:
double-blind treatment period inclusion criteria: 1. male and non-pregnant female subjects, aged 16 to 65 years with a genetically proven diagnosis of cmt1a. notes: a) a report of a genetic test confirming pmp22 duplication and therefore a diagnosis of cmt1a must be available in the subject's record at the clinical site. b) in the absence of a report of a genetic test confirming pmp22 duplication in the subject's medical record, a confirmatory genetic test must be conducted via the central laboratory as part of screening. c) in the exceptional case wherein subject was randomized into the study without meeting(a) or (b), an unscheduled confirmatory genetic test will be performed. in the event of a negative genetic test result, the subject will be withdrawn from the study. 2. able to provide written informed consent/assent and comply with study procedures. 3. mild-to-moderate severity assessed by a cmtns-v2 score \>2 and ≤18. 4. muscle weakness in at least foot dorsiflexion on clinical assessment. 5. ulnar nerve motor conduction time of at least 15 m/s. 6. if taking prescribed psychoactive drugs(eg, antidepressants, stimulants, tranquilizers, anti-epileptics) for cmt1a, should be on a stable dose for at least 4 weeks prior to randomization, which is not planned to be changed. 7. if taking prescribed or 'over-the-counter' analgesic medications (eg, paracetamol/acetaminophen, nonsteroidal anti-inflammatory drugs) for cmt1a, should be on a stable dose for at least 2 weeks prior to randomization, which is not planned to be changed. 8. if female, subject must be: (a) surgically sterilized via hysterectomy, bilateral oophorectomy, or bilateral tubal ligation; or (b) of childbearing potential and using a birth control method such as: * combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: * oral * intravaginal * transdermal * progestogen-only hormonal contraception associated with inhibition of ovulation: * oral * injectable * implantable * intrauterine device * intrauterine hormone-releasing system * bilateral tubal occlusion * vasectomized partner * sexual abstinence or (c) of non-childbearing potential (i.e., no menses for ≥ 12 consecutive months without any other underlying medical cause) 9. if male, the subject must have had a vasectomy or must use a reliable method of birth control with their partner or total abstinence from sexual intercourse. the subject must agree to continue using their selected method of birth control with their sexual partner during the study and for 120 days after study completion. exclusion criteria: 1. subjects previously enrolled in any pxt3003 study. 2. subjects living in the same household and enrolled in a pxt3003 study (due to potential lack of adequate storage for study material, risk of mixing treatments and potential unblinding). 3. cmt of any subtype other than 1a. 4. onls score of 0. 5. known clinically significant motor or sensory abnormalities secondary to a different neurological cause (eg, diabetes, alcohol, vascular, autoimmune, neoplastic, neurodegenerative, human immunodeficiency virus, etc.). note: subjects with diagnosis of unilateral carpal tunnel syndrome at least 1 year prior to screening visit, that is asymptomatic at the time of screening visit, will not be excluded from participating in this study. 6. subjects who have had any surgery or have a concomitant disorder (eg, severe arthrosis) that reduces the mobility of the ankle or wrist making it, in the opinion of the investigator, difficult to assess the efficacy of the treatment. note: subjects with surgical repair of unilateral carpel tunnel syndrome will not be excluded from participating in this study. 7. known peripheral neuropathy, myopathy, or neuromuscular disorder of any other kind. note: subjects with diagnosis of unilateral carpal tunnel syndrome at least 1year prior to screening visit, that is asymptomatic at the time of screening visit, will not be excluded from participating in this study. 8. any other clinically significant and/or uncontrolled medical condition that, in the opinion of the investigator, could be a confound, may increase subject's risk, or may preclude successful participation or completion of the study. 9. known hypersensitivity or intolerance to pxt3003( or matching placebo), including any of its active ingredients( baclofen, naltrexone, or sorbitol), and/or any of its excipients( acetate buffer, sodium methyl parahydroxybenzoate, sodium propyl parahydroxybenzoate, or isoamyl acetate). 10. concomitant treatments including but not limited to baclofen, naltrexone, sorbitol (pharmaceutical form), opioids, potent central nervous system depressants (such as barbiturates, long-acting benzodiazepines, and neuroleptics), and potentially neurotoxic drugs such as amiodarone, chloroquine, and chemotherapeutics capable of inducing peripheral neuropathy. subjects able to stop these medications at least 2 weeks before randomization and for the study duration may be included. subjects with positive urine drug screen at baseline visit will be excluded, except for permitted use of codeine and benzodiazepines. 11. history of porphyria. 12. diagnosis or history of substance use disorder by diagnostic and statistical manual of mental disorders-5th edition criteria within the past 12 months. 13. medical or recreational use of marijuana in the 3 months prior to the screening visit. 14. active suicidality (eg, any suicide attempts within the past 12 months or any current suicidal intent, including a plan, as assessed by the c ssrs score of "yes" on questions 4 or 5; and/or based on clinical evaluation by the investigator). 15. currently active major depression, as determined by a beck depression inventory-ii (bdi-ii) score ≥20. 16. currently lactating, pregnant, or planning on becoming pregnant during the study. 17. alanine aminotransferase or aspartate aminotransferase levels greater than 2 times the upper limit of normal. 18. significant renal impairment as determined by glomerular filtration rate of less than 50 ml/min. 19. subject has participated in an investigational drug or device study within 30 days prior to the screening visit or plans to participate in an investigational drug or device study during the course of this study. 20. subject is a dependent and/or relative of the sponsor or principal investigator. ole period inclusion criteria: 1. able to provide written informed consent/assent and comply with study procedures. 2. if female, subject must be (a) surgically sterilized via hysterectomy, bilateral oophorectomy, or bilateral tubal ligation; or (b) of childbearing potential and using a birth control method such as: * combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: * oral * intravaginal * transdermal * progestogen-only hormonal contraception associated with inhibition of ovulation: * oral * injectable * implantable * iud * ius * bilateral tubal occlusion * vasectomized partner * sexual abstinence or (c) of non-childbearing potential (ie, no menses for ≥12 consecutive months without any other underlying medical cause). 3. if male, the subject must have had a vasectomy or must use a reliable method of birth control with their partner or total abstinence from sexual intercourse. the subject must agree to continue using their selected method of birth control with their sexual partner during the study and for 120 days after study completion. exclusion criteria: 1. any clinically significant and/or uncontrolled medical condition that, in the opinion of the investigator, could be a confound factor, may increase subject's risk, or may preclude successful participation or completion of the study. 2. concomitant treatments including but not limited to baclofen, naltrexone, sorbitol (pharmaceutical form) other than pxt3003 taken in the double-blind treatment period of this study, opioids, potent cns depressants (such as barbiturates, long-acting benzodiazepines, and neuroleptics), and potentially neurotoxic drugs such as amiodarone, chloroquine, and chemotherapeutics capable of inducing peripheral neuropathy. subjects able to stop these medications at least 2 weeks before randomization and for the study duration may be included. 3. diagnosis or history of substance use disorder by diagnostic and statistical manual of mental disorders-5ᵗʰ edition criteria within the past 12 months. 4. active suicidality (eg, any suicide attempts within the past 12 months or any current suicidal intent, including a plan, as assessed by the c-ssrs score of "yes" on questions 4 or 5; and/or based on clinical evaluation by the investigator). 5. currently active major depression, as determined by a bdi-ii score ≥20. 6. currently lactating, pregnant, or planning on becoming pregnant during the study. 7. alt or ast levels greater than 2 × uln relative to baseline. 8. estimated gfr of less than 50 ml/min. note: pxt3003 will be dispensed to all subjects before laboratory results are available, and if the laboratory results are out of range, ie, subject meeting the exclusion criteria, the subject will be called immediately to stop taking pxt3003. one retest within 4 weeks may be performed in consultation with the medical monitor if any of the above laboratory abnormalities are found. in case of eligibility determination after the retest, subjects will restart taking 2 weeks of half dose of pxt3003.

Keywords: charcot marie tooth type 1 peripheral neuropathy pxt3003